Pyridinamine-pyridone and pyrimidinamine- pyridone compounds

ABSTRACT

The invention provides novel pyridinamine-pyridone and pyrimidinamine-pyridone compounds of formula (I), pharmaceutical compositions containing such compounds, and methods for using such compounds in treatment of diseases including cancer, type II diabetes, inflammatory disease, neurodegenerative disorders, cardiovascular disorders, autoimmune diseases and viral infections; (I) wherein R 1 , R 2 , R 3  and Z are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 national phase of International ApplicationNo. PCT/EP2018/072790, filed on Aug. 23, 2018, which claims the benefitof European Patent Application No. 17187560.2, filed on Aug. 23, 2017,which applications are incorporated by reference herein.

FIELD OF THE INVENTION

The invention provides novel pyridinamine-pyridone andpyrimidinamine-pyridone compounds of formula (I), pharmaceuticalcompositions containing such compounds, and methods for using suchcompounds in treatment of diseases including cancer and type IIdiabetes.

BACKGROUND OF THE INVENTION

Enzymes belonging to the family of phosphatidylinositide 3-kinases(PI3K) are regulators of several important cellular events. The familyconsists of three classes, I, II and III and while the Class I group hasbeen an interesting drug target for many years, Class II and III areless exploited. The PI3K Class III, vacuolar protein sorting 34 (Vps34,PIK3C3) forms a heterodimer with its regulatory subunit p150 (Vps15) andthis dimer takes part in several complexes regulating vesiculartrafficking events such as autophagy, endocytosis, exocytosis andmicropinocytosis (Amaravadi et al. Clin Cancer Res. 2011, 17:654-666;Carpentier et al. 2013, Traffic). The enzyme is responsible forphosphorylation of phosphatidylinositol (PI) to phosphatidylinositol(3)-phosphate (PI3P). The ligand binding to PX and FYVE domains resultsin recruiting and delocalization of these effector proteins that lead tovesicular formation, elongation and movement (Backer et al. J Biochem.2008, 410:1-17).

Autophagy is a catabolic process where cellular components are targetedfor degradation by enclosing them in double-membrane vesicles,auto-phagosomes that are fused with the protease-containing lysosomes.This is a mean for the cell to handle damaged organelles and misfoldedproteins and by that maintain cellular function. The pathway is also away of recirculating cellular content into new building blocks (Boya etal, Nat Cell Biol 2013, 15; 713-720). Autophagy is a cellular responseto stressful conditions as nutrient deprivation, acidosis and hypoxiabut also to drug treatment. Therefore, autophagy inhibition is a meansto potentiate cancer drugs and resensitize drug resistant tumors(Nagelkerke et al, Semin Cancer Biol 2014, 31; 99-105). Most advancedtumors show a high upregulation of autophagic flux (Leone et al. Trendsin Endocrin Metab 2013, 24; 209-217). An established marker for studyingautophagic flux is the detection of autophagic puncta in the form oflipidated LC3 protein on the autophagosome. Inhibition of Vps34 resultsin the inhibition of autophagy as measured by LC3 redistribution intopuncta (Dowdle et al., Nat Cell Biol 2014, 16; 1069-79).

As recently described, ablation of the regulatory subunit p150 leads toincreased insulin sensitivity in vivo due to decreased insulin receptorinternalization (Nemazanyy, Nature Commun., 2015, 6:8283). A kinase deadheterozygous animal model confirms this result with increased glucosetolerance and increased insulin sensitivity (WO2013076501).

Several disease states could benefit from Vps34 inhibition includingcancer, inflammatory diseases, neurodegenerative disorders,cardiovascular disorders, diabetes, such as type II diabetes, and viralinfections (Reviewed in Rubinsztein et al, Nat Rev 2012, 11; 709-730).Cancer forms that would benefit from Vps34 inhibition include, but arenot limited to, breast cancer, such as triple negative breast cancer,bladder cancer, liver cancer, cervical cancer, pancreatic cancer,leukemia, lymphoma, renal cancer, colon cancer, glioma, prostate cancer,ovarian cancer, melanoma, and lung cancer as well as hypoxic tumors.There is thus a need for novel and potent inhibitors of Vps34.

Previous disclosures describing Vps34 inhibitors in use to affectdiseases include WO2015150555; WO2015150557; WO2015108861; WO2015108881;WO2012085815; WO2012085244; WO2013190510; Farkas, J. Biol. Chem., 2011286(45) 38904-12.

DESCRIPTION OF THE INVENTION

An object of the invention is to provide novel and potent inhibitors ofVps34. Another object of the invention is to provide novel and potentinhibitors of Vps34 that may be used for treating cancer and otherdiseases such as type II diabetes.

According to aspect 1 of the invention, there is provided a compound ofFormula (I)

wherein

R¹ is phenyl or monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₃-C₄cycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, amino, N—C₁-C₃alkylamino and N,N-diC₁-C₃alkylamino;

R² is selected from hydrogen, C₁-C₃haloalkyl and C₁-C₃alkyl;

R³ is selected from A, phenyl and monocyclic heteroaryl, said phenyl andsaid heteroaryl being each optionally substituted with one or more ofR⁴, R⁵, R⁶ and R⁷;

R⁴, R⁵, R⁶ and R⁷ are independently selected from halogen, C₁-C₆alkyl,C₃-C₄cycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy,azetidine, amino, N—C₁-C₃alkylamino, N,N-diC₁-C₃alkylamino, NHSO₂R⁸,SO₂R⁹ and hydroxy;

R⁸ is C₁-C₃haloalkyl or C₁-C₃alkyl;

R⁹ is selected from R¹⁰, C₁-C₆alkyl, amino, N—C₁-C₃alkylamino,N,N-diC₁-C₃alkylamino and C₁-C₃alkoxyC₁-C₃alkyl, wherein said C₁-C₆alkyland C₁-C₃alkoxyC₁-C₃alkyl being each optionally substituted with one R¹⁰and/or one or more halogen;

R¹⁰ is selected from phenyl, benzyl, monocyclic heteroaryl,C₃-C₆cycloalkyl, heterocyclyl, each optionally substituted with one ormore R¹¹;

R¹¹ is selected from halogen, C₁-C₃haloalkyl, C₃-C₄cycloalkyl,C₁-C₃alkyl, amino, N—C₁-C₃alkylamino, N,N-diC₁-C₃alkylamino andC₁-C₃alkoxyC₁-C₃alkyl;

A is

R¹² is selected from hydrogen, halogen, COR¹³, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₁-C₃alkoxyC₁-C₃alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,C₁-C₃cyanoalkyl, and C₁-C₃haloalkyl;

R¹³ is selected from C₁-C₃alkoxy, N—C₁-C₃alkylamino,N,N-diC₁-C₃alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl;

Y is selected from CH₂, S, SO, SO₂, NR¹⁴, NCOR⁹, NCOOR¹⁵, NSO₂R⁹,NCOCH₂R⁹, O, or a bond;

R¹⁴ is selected from H, C₁-C₃haloalkyl, C₁-C₃alkoxyC₁-C₃alkyl,C₁-C₃alkyl, and C₃-C₆cycloalkyl; and

R¹⁵ is selected from R¹⁰, C₁-C₆alkyl and C₁-C₃alkoxyC₁-C₃alkyl, andwherein said C₁-C₆alkyl and C₁-C₃alkoxyC₁-C₃alkyl being each optionallysubstituted with one R¹⁰ and/or one or more halogen; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 2 of the invention, there is provided a compound ofFormula (I), such as according to aspect 1, wherein R² is hydrogen orC₁-C₃alkyl.

According to aspect 3 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 or 2, wherein R²is hydrogen.

According to aspect 4 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 3, wherein R¹is phenyl or a monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₃-C₄cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,C₁-C₆haloalkoxy, amino, —N—C₁-C₃alkylamino, N,N-di-C₁-C₃alkylamino andhalogen.

According to aspect 5 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 4, wherein R¹is phenyl or a monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from C₁-C₆alkyl,C₃-C₄cycloalkyl, and halogen.

According to aspect 6 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R³is selected from

According to aspect 7 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 6, wherein R³is selected from

According to aspect 8 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R³is selected from

Y is selected from CH₂, NSO₂R⁹, O and a bond;

R⁴ is selected from CF₃, fluoro, cyclopropyl and methyl;

R⁵ is fluoro;

R⁹ is selected from C₁-C₆alkyl, phenyl, and benzyl, each optionallysubstituted with one or more halogen; and

R¹² is selected from hydrogen, methyl, cyclopropyl and CF₃.

According to aspect 9 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R³is selected from

Y is selected from NSO₂R⁹, CH₂ and O;

R⁴ is selected from cyclopropyl, CF₃ and chloro;

R⁵ is fluoro;

R⁹ is selected from C₁-C₆alkyl, phenyl, and benzyl, each optionallysubstituted with one or more halogen; and

R¹² is cyclopropyl or CF₃.

According to aspect 10 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R³is

R⁹ is selected from C₁-C₆alkyl, phenyl, and benzyl, wherein said phenyland benzyl group may optionally be substituted with one or more halogen,C₁-C₆alkyl, C₁-C₆haloalkyl and C₃-C₄cycloalkyl; and

R¹² is selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl andC₃-C₄cycloalkyl.

According to aspect 11 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 10, wherein R¹is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl, pyrazolyland thiazolyl, each optionally substituted with one or more substituentsselected from halogen, C₁-C₆alkyl, C₃-C₄cycloalkyl, and C₁-C₆haloalkyl.

According to aspect 12 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 11, wherein R¹is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl, andthiazolyl, each optionally substituted with one or more substituentsselected from halogen, C₁-C₆alkyl, C₃-C₄cycloalkyl, and C₁-C₆haloalkyl.

According to aspect 13 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R³is selected from A, phenyl, pyridyl, thienyl, furyl, pyrimidinyl andpyrazolyl, each optionally and independently substituted with one ormore R⁴ or R⁵.

According to aspect 14 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 8, wherein R³is selected from A, phenyl and pyridyl, each optionally andindependently substituted with one or more R⁴ or R⁵.

According to aspect 15 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 8, wherein R³is selected from phenyl, pyridyl, morpholinyl, piperidyl, pyrrolidinyl,thienyl, and piperazinyl, each optionally substituted with one or moresubstituents selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl andC₃-C₄cycloalkyl.

According to aspect 16 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R⁴,R⁵, R⁶ and R⁷ are independently selected from fluoro, chloro,C₁-C₃alkyl, C₁-C₃fluoroalkyl, cyclopropyl and SO₂R⁹.

According to aspect 17 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 8, aspect 13,aspect 14, or aspect 16, wherein Y is selected from CH₂, O and a bond.

According to aspect 18 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, or aspect13, wherein R¹² is selected from hydrogen, CON(CH₃)₂, C₁-C₃alkyl, CF₃and cyclopropyl.

According to aspect 19 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, aspect 13,aspect 14, or aspect 16, wherein R⁹ is selected from R¹⁰,N,N-diC₁-C₃alkylamino and methoxyC₁-C₃alkyl, said C₁-C₃alkyl beingoptionally substituted with one R¹⁰.

According to aspect 20 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, aspect 13,aspect 14, aspect 16, or aspect 19, wherein R¹⁰ is selected from phenyl,benzyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl,cyclopentyl, pyrrolidinyl, and tetrahydrofuryl, each optionallysubstituted with one or more methyl and/or fluoro.

According to aspect 21 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R³is selected from phenyl, pyridyl, pyrrolidinyl and thienyl, eachoptionally substituted with one or more substituents selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl and C₃-C₄cycloalkyl; or A;

Y is CH₂, O, NSO₂—C₁-C₆alkyl or NSO₂-benzyl, wherein said benzyl isoptionally substituted by one or more halogen; and

R¹² is C₁-C₆alkyl or C₁-C₆haloalkyl.

According to aspect 22 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 3, wherein R¹is phenyl or a monocyclic 5-6 membered heteroaryl each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₃-C₄cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,C₁-C₆haloalkoxy, amino, N—C₁-C₃alkylamino, N,N-di-C₁-C₃alkylamino andhalogen;

R² is hydrogen;

R³ is phenyl or monocyclic 5-6 membered heteroaryl each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl and C₃-C₄cycloalkyl.

According to aspect 23 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl or a monocyclic 5-6 membered heteroaryl each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl;

R² is hydrogen; and

R³ is phenyl or monocyclic 5-6 membered heteroaryl each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl and C₃-C₄cycloalkyl.

According to aspect 24 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R¹is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl, orthiazolyl, each optionally substituted with one or more substituentsselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl;

R² is hydrogen;

R³ is selected from phenyl, pyridyl, pyrazolyl pyrrolidinyl, andthienyl, each optionally substituted with one or more substituentsselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₄cycloalkyl; orA;

Y is CH₂, O, NSO₂—C₁-C₆alkyl or NSO₂-benzyl, wherein said benzyl isoptionally substituted by one or more halogen; and

R¹² is C₁-C₆alkyl or C₁-C₆haloalkyl.

According to aspect 25 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is selected from phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl,2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl,2-methyl-thiazol-4-yl, 3,5-difluorophenyl and 2-methylpyrazol-3-yl;

R² is hydrogen; and

R³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl,3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl,2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl,2-(trifluoromethyl)-pyridin-3-yl,1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl,4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl,2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro-5-fluorophenyl,3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl,3-methyl-thien-4-yl, 2-methylphenyl,1-acetyl-3-trifluoromethyl-piperazin-4-yl, 2-methyl-piperidin-1-yl,2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl,2-trifluoromethyl-morpholin-4-yl, and 2-cyclopropyl-morpholin-4-yl.

According to aspect 26 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is selected from phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl,2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl,2-methyl-thiazol-4-yl, and 3,5-difluorophenyl;

R² is hydrogen; and

R³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl,3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl,2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl,2-(trifluoromethyl)-pyridin-3-yl,1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl,4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl,2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro-5-fluorophenyl,3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl,3-methyl-thien-4-yl, 2-methylphenyl,1-acetyl-3-trifluoromethyl-piperazin-4-yl, 2-methyl-piperidin-1-yl,2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl,2-trifluoromethyl-morpholin-4-yl, and 2-cyclopropyl-morpholin-4-yl.

According to aspect 27 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl or monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl;

R² is hydrogen;

R³ is phenyl or monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 28 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl, or pyrimidinyl, each optionally substituted with one or moresubstituents selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₃-C₄cycloalkyl;

R² is hydrogen;

R³ is selected from phenyl, pyridyl and pyrazolyl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl; or A;

Y is CH₂, O, NSO₂—C₁-C₆alkyl or NSO₂-benzyl, wherein said benzyl isoptionally substituted by one or more halogen;

R¹² is C₁-C₆alkyl or C₁-C₆haloalkyl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 29 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl, 3,5-difluorophenyl or 2-methylpyrimidin-4-yl;

R² is hydrogen;

R³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl,2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl,4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl,2-(trifluoromethyl)phenyl, 4-methyl-3-pyridyl,2-(trifluoromethyl)-3-pyridyl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl,and 3-cyclopropylmorpholin-4-yl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 30 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl or monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl;

R² is hydrogen;

R³ is phenyl or monocyclic 5-6 membered heteroaryl, each optionallysubstituted with one or more substituents selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, and C₃-C₄cycloalkyl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 31 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl, or pyrimidinyl, each optionally substituted with one or moresubstituents selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, andC₃-C₄cycloalkyl;

R² is hydrogen;

R³ is selected from phenyl or pyridyl, each optionally substituted withone or more substituents selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₃-C₄cycloalkyl; or A;

Y is CH₂, O, NSO₂—C₁-C₆alkyl or NSO₂-benzyl, wherein said benzyl isoptionally substituted by one or more halogen;

R¹² is C₁-C₆alkyl or C₁-C₆haloalkyl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 32 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl, 2-methylpyrimidin-4-yl, oxazol-2yl, 2-methylthiazol-4-yl,2-methylpyrazol-3-yl, and 1-methylimidazol-4-yl;

R² is hydrogen;

R³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl,2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl,4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl;2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl,2-(trifluoromethyl)-pyridin-3-yl and1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 33 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 7, wherein R¹is phenyl, or 2-methyl pyrimidin-4-yl;

R² is hydrogen;

R³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl,2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl,and 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl; and

Z is CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 34 of the invention, there is provided a compoundselected from:

-   4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one-   4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)¬phenyl]-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;-   4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;-   6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;-   6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;    and-   6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 35 of the invention, there is provided a compoundselected from:

-   4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one-   4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)¬phenyl]-1H-pyridin-2-one;-   6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;-   6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;    and-   6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 36 of the invention, there is provided a compoundselected from:

-   4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one-   4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;-   4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   4-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;-   6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)¬phenyl]-1H-pyridin-2-one;-   6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;-   4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;-   6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;    and-   6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 37 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R³is selected from

According to aspect 38 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R⁴is selected from chloro, CF₃ and methyl; R⁵ is C₁-C₃alkyl, such asethyl; and R¹² is hydrogen or CF₃.

According to aspect 39 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein Yis selected from CH₂, O and NSO₂R⁹.

According to aspect 40 of the invention, there is provided a compound ofFormula (I), such as according to any one of aspects 1 to 5, wherein R⁹is selected from C₁-C₃alkyl and benzyl, said benzyl beingmeta-substituted with fluoro.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in the treatment or prophylaxis of adisease.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating cancer. Typically, saidcancer is selected from breast cancer, such as triple negative breastcancer, bladder cancer, liver cancer, cervical cancer, pancreaticcancer, leukemia, lymphoma, renal cancer, colon cancer, glioma, prostatecancer, ovarian cancer, melanoma and lung cancer, as well as hypoxictumors.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating hypoxic tumors.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating type II diabetes.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating a disease selected frominflammatory diseases, neurodegenerative disorders, cardiovasculardisorders, autoimmune diseases and viral infections.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating cancer. Typically said cancer is selected from breastcancer, such as triple negative breast cancer, bladder cancer, livercancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, renalcancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanomaand lung cancer, as well as hypoxic tumors.

In one aspect of the invention, there is provided a compound accordingto the present invention, in the preparation of a medicament fortreating hypoxic tumors.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating type II diabetes.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating a disease selected from inflammatory diseases,neurodegenerative disorders, cardiovascular disorders, autoimmunediseases and viral infections.

In one aspect of the invention, there is provided a method of treatingcancer, comprising administering a therapeutically effective amount of acompound according to the present invention, to a patient in needthereof. Typically, said cancer is selected from breast cancer, such astriple negative breast cancer, bladder cancer, liver cancer, cervicalcancer, pancreatic cancer, leukemia, lymphoma, renal cancer, coloncancer, glioma, prostate cancer, ovarian cancer, melanoma and lungcancer, as well as hypoxic tumors.

In one aspect of the invention, there is provided a method of treatinghypoxic tumors, comprising administering a therapeutically effectiveamount of a compound according to the present invention, to a patient inneed thereof.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating cancer, wherein saidcancer treatment further comprises radiation therapy.

In one aspect of the invention, there is provided a method of treatingcancer, comprising administering a therapeutically effective amount of acompound according to the present invention, to a patient in needthereof, in conjunction with radiation therapy.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention. Generally, the use of cytotoxic and/or cytostatic agentsin combination with a compound or composition of the present inventionwill serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

In one aspect of the invention, there is provided a method of treatingtype II diabetes, comprising administering a therapeutically effectiveamount of a compound according to the present invention, to a patient inneed thereof.

In one aspect of the invention, there is provided a method of treating adisease selected from inflammatory diseases, neurodegenerativedisorders, autoimmune diseases and viral infections, comprisingadministering a therapeutically effective amount of a compound accordingto the present invention, to a patient in need thereof.

In one aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound according to the present invention,and a pharmaceutically acceptable diluent, carrier and/or excipient.

In one aspect of the invention, there is provided a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to the present invention and another anticancer agent selectedfrom alkylating agents, antimetabolites, anticancer camptothecinderivatives, plant-derived anticancer agents, antibiotics, enzymes,platinum coordination complexes, tyrosine kinase inhibitors, hormones,hormone antagonists, monoclonal antibodies, interferons, and biologicalresponse modifiers.

As used herein, the term “C₁-C₆alkyl” means both linear and branchedchain saturated hydrocarbon groups with 1 to 6 carbon atoms. Examples ofC₁-C₆alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, t-butyl, n-pentyl, 4-methyl-butyl, n-hexyl,2-ethyl-butyl groups. Among unbranched C₁-C₆alkyl groups, typical onesare methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Amongbranched alkyl groups, there may be mentioned iso-propyl, iso-butyl,sec-butyl, t-butyl, 4-methyl-butyl and 2-ethyl-butyl groups.

As used herein, the term “C₁-C₃alkyl” means both linear and branchedchain saturated hydrocarbon groups with 1 to 3 carbon atoms. Examples ofC₁-C₃alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.

As used herein, the term “C₁-C₆alkoxy” means the group O—C₁-C₆alkyl,where “C₁-C₆alkyl” is used as described above. Examples of C₁-C₆alkoxygroups include, but are not limited to, methoxy, ethoxy, isopropoxy,n-propoxy, n-butoxy, n-hexoxy, 3-methyl-butoxy groups.

As used herein, the term “C₁-C₃alkoxy” means the group O—C₁-C₃alkyl,where “C₁-C₃alkyl” is used as described above. Examples of C₁-C₃alkoxygroups include, but are not limited to, methoxy, ethoxy, isopropoxy andn-propoxy.

As used herein, the term “C₁-C₆haloalkyl” means both linear and branchedchain saturated hydrocarbon groups, with 1 to 6 carbon atoms and with 1to all hydrogens substituted by a halogen of different or same type.Examples of C₁-C₆haloalkyl groups include methyl substituted with 1 to 3halogen atoms, ethyl substituted with 1 to 5 halogen atoms, n-propyl oriso-propyl substituted with 1 to 7 halogen atoms, n-butyl or iso-butylsubstituted with 1 to 9 halogen atoms, and sec-butyl or t-butyl groupssubstituted with 1 to 9 halogen atoms.

As used herein, the term “C₁-C₃haloalkyl” means both linear and branchedchain saturated hydrocarbon groups, with 1 to 3 carbon atoms and with 1to all hydrogens substituted by a halogen of different or same type.Examples of C₁-C₃haloalkyl groups include methyl substituted with 1 to 3halogen atoms, ethyl substituted with 1 to 5 halogen atoms, and n-propylor iso-propyl substituted with 1 to 7 halogen atoms.

As used herein, the term “C₁-C₃haloalkoxy” means both linear andbranched chain saturated alkoxy groups, with 1 to 3 carbon atoms andwith 1 to all hydrogen atoms substituted by a halogen atom of differentor same type. Examples of C₁-C₃haloalkoxy groups include methoxysubstituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5halogen atoms, and n-propoxy or iso-propoxy substituted with 1 to 7halogen atoms.

As used herein, the term “C₁-C₃fluoroalkyl” means both linear andbranched chain saturated hydrocarbon groups, with 1 to 3 carbon atomsand with 1 to all hydrogen atoms substituted by a fluorine atom.Examples of C₁-C₃fluoroalkyl groups include methyl substituted with 1 to3 fluorine atoms, ethyl substituted with 1 to 5 fluorine atoms, andn-propyl or iso-propyl substituted with 1 to 7 fluorine atoms.

As used herein, the term “C₁-C₃fluoroalkoxy” means both linear andbranched chain saturated alkoxy groups, with 1 to 3 carbon atoms andwith 1 to all hydrogen atoms substituted by a fluorine atom. Examples ofC₁-C₃fluoroalkoxy groups include methoxy substituted with 1 to 3fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, andn-propoxy or iso-propoxy substituted with 1 to 7 fluorine atoms.

As used herein, the term “C₃-C₆cycloalkyl” means a cyclic saturatedhydrocarbon group, with 3 to 6 carbon atoms. Examples of C₃-C₆cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “C₁-C₃alkoxyC₁-C₃alkyl” means both a linear andbranched chain saturated hydrocarbon group, with 1 to 3 carbon atoms,substituted with an alkoxy group with 1 to 3 carbon atoms. Examples ofC₁-C₃alkoxyC₁-C₃alkyl groups are drawn below.

As used herein, the term “C₁-C₃cyanoalkyl” means both a linear andbranched chain cyano (CN) derivative, with one to three carbon atomsincluding the carbon atom that is part of the cyano group. Examples ofC₁-C₃cyanoalkyl groups are drawn below.

As used herein, the term N—C₁-C₃alkylamino means an amino substituentcarrying one C₁-C₃alkyl group as defined supra. Examples ofN—C₁-C₃alkylamino are drawn below.

As used herein, the term N,N-diC₁-C₃alkylamino means an aminosubstituent carrying two C₁-C₃alkyl groups as defined supra. Examples ofN,N-diC₁-C₃alkylamino are drawn below.

As used herein, the term “halogen” means fluorine, chlorine, bromine oriodine. It is to be understood that when a substituent is halogen (orhalo), it is always bound to a carbon atom.

As used herein, the term “aryl” means a monocyclic aromatic carbocyclicgroup. An examples of such group include phenyl.

As used herein, the term “monocyclic aryl” means a monocyclic aromaticcarbocyclic group. Examples of monocyclic aryl groups include phenyl.

As used herein, the term “heteroaryl” means a monocyclic or bicyclicaromatic group of carbon atoms wherein from one to three of the carbonatoms is/are replaced by one or more heteroatoms independently selectedfrom nitrogen, oxygen or sulfur. In a bicyclic aryl, one of the ringsmay be partially saturated.

Examples of such groups include indolinyl, dihydrobenzofuran and1,3-benzodioxolyl.

As used herein, the term “monocyclic heteroaryl” means a monocyclicaromatic group of carbon atoms wherein from one to three of the carbonatoms is/are replaced by one or more heteroatoms independently selectedfrom nitrogen, oxygen or sulfur.

Examples of monocyclic heteroaryl groups include, but are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl,isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

Examples of bicyclic heteroaryl groups include, but are not limited to,quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl,benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl,indolyl, indazolyl, benzothiazolyl, pyridopyrimidinyl, andisoquinolinyl.

As used herein, the term “heterocyclyl” means a cyclic group of carbonatoms wherein from one to three of the carbon atoms is/are replaced byone or more heteroatoms independently selected from nitrogen, oxygen andsulfur. Examples of heterocyclyl groups include, but are not limited to,tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and dioxanyl.

Depending on the substituents present in compounds of the formula (I),the compounds may form salts which are within the scope of the presentinvention. Salts of compounds of formula (I), which are suitable for usein medicine are those wherein a counterion is pharmaceuticallyacceptable.

Suitable salts according to the invention include those formed withorganic or inorganic acids or bases. In particular, suitable saltsformed with acids according to the invention include those formed withmineral acids, strong organic carboxylic acids, such as alkanecarboxylicacids of 1 to 4 carbon atoms which are unsubstituted or substituted, forexample, by halogen, such as saturated or unsaturated dicarboxylicacids, such as hydroxycarboxylic acids, such as amino acids, or withorganic sulfonic acids, such as (C₁-C₄)alkyl or aryl sulfonic acidswhich are unsubstituted or substituted, for example by halogen.Pharmaceutically acceptable acid addition salts include those formedfrom hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric,acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic,perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic,methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic,malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic,malic, phthalic, aspartic, and glutamic acids, lysine and arginine.

Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, for example those of potassium and sodium, alkaline earthmetal salts, for example those of calcium and magnesium, and salts withorganic bases, for example dicyclohexylamine, N-methyl-D-glucamine,morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or trilower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl,triethyl, tributyl or dimethylpropylamine, or a mono-, di- or trihydroxylower alkylamine, for example mono-, di- or triethanolamine.Corresponding internal salts may furthermore be formed.

The compounds of the invention may be used in the prophylaxis and/ortreatment as such, or in a form of a pharmaceutical composition. Whileit is possible for the active ingredient to be administered alone, it isalso possible for it to be present in a pharmaceutical composition.Accordingly, the invention provides a pharmaceutical compositioncomprising a compound of formula (I), and a pharmaceutically acceptablediluent, excipient and/or carrier. Pharmaceutical compositions of theinvention may take the form of a pharmaceutical composition as describedbelow.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactoseand/or other excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Disintegrators include without limitation starch,methylcellulose, agar, bentonite, xanthan gum and the like. Thecompounds of formula (I) can also be delivered through the oral cavityby sublingual and/or buccal administration. Molded tablets, compressedtablets or freeze-dried tablets are exemplary forms which may be used.Exemplary compositions include those formulating the present compound(s)with fast dissolving diluents such as mannitol, lactose, sucrose and/orcyclodextrins. Also included in such compositions may be high molecularweight excipients such as celluloses (avicel) or polyethylene glycols(PEG). Such compositions can also include an excipient to aid mucosaladhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methylcellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleicanhydride copolymer (e.g., Gantrez), and agents to control release suchas polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use. Lubricants used in these dosage forms includesodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride and the like. For oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, pills ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution or a suspension in an aqueousliquid or a non-aqueous liquid, for example as elixirs, tinctures,suspensions or syrups; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The present compounds can, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release can be achieved by theuse of suitable pharmaceutical compositions comprising the presentcompounds, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentcompounds can also be administered liposomally.

Typical unit dosage compositions are those containing an effective dose,as hereinbefore recited, or an appropriate fraction thereof, of theactive ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions of this invention may include otheragents conventional in the art having regard to the type of compositionin question, for example those suitable for oral administration mayinclude flavoring agents.

The compositions may be presented in unit dosage form and may beprepared by any of the methods well known in the art of pharmacy.Methods may include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. Compositions may be prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired composition.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids,1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine(cephaline), phosphatidylserine, phosphatidylinositol,diphosphatidylglycerol (cardiolipin) or phosphatidylcholine (lecithin).

Compositions for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the composition isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Exemplary compositions for parenteraladministration include injectable solutions or suspensions which cancontain, for example, suitable non-toxic, parenterally acceptablediluents or solvents, such as polyethylene glycol, ethanol,1,3-butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid, or Cremaphor.

Exemplary compositions for nasal, aerosol or inhalation administrationinclude solutions in saline, which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Compositions for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, synthetic glyceride estersor polyethylene glycol. Such carriers are typically solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Compositions for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerine or sucrose and acacia. Exemplary compositions fortopical administration include a topical carrier such as Plastibase(mineral oil gelled with polyethylene).

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thispharmaceutical composition includes administration of a singlepharmaceutical dosage composition which contains a compound of formula(I) and one or more additional therapeutic agents, as well asadministration of the compound of formula (I) and each additionaltherapeutic agent in its own separate pharmaceutical dosage composition.For example, a compound of formula (I) and a therapeutic agent may beadministered to the patient together in a single oral dosage compositionsuch as a capsule or tablet, or each agent may be administered incompositions with separate dosage.

Where separate dosage compositions are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

The amount of active ingredient which is required to achieve atherapeutic effect will, of course, vary with the particular compound,the route of administration, the subject under treatment, including thetype, species, age, weight, sex, and medical condition of the subjectand the renal and hepatic function of the subject, and the particulardisorder or disease being treated, as well as its severity. Anordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of bodyweight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to5.0 mg/kg/day, for adult humans. For oral administration, thecompositions may be provided in the form of tablets or other forms ofpresentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. A medicament typically contains from about 0.01mg to about 500 mg of the active ingredient, preferably from about 1 mgto about 100 mg of active ingredient. Intravenously, the most preferreddoses will range from about 0.1 to about 10 mg/kg/minute during aconstant rate infusion. Compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

Preparation of Compounds

The compounds in the present invention can be prepared as a free base ora pharmaceutically acceptable salt thereof by the process describedbelow.

Throughout the following description of such processes it is understoodthat, where appropriate, suitable protecting groups will be added to,and subsequently removed from the various reactants and intermediates ina manner that will be readily understood by one skilled in the art oforganic synthesis. Conventional procedures for using such protectinggroups as well as examples of suitable protecting groups are for exampledescribed in Protective Groups in Organic Synthesis by T. W. Greene, P.G. M Wutz, 4^(th) Edition, Wiley-Interscience, New York, 2006. It isunderstood that microwaves can alternatively be used for the heating ofreaction mixtures.

Another aspect of the present invention provides a process for preparinga compound of formula (I), or a pharmaceutically acceptable saltthereof, wherein R¹, R², R³, and Z are, unless specified otherwise, asdefined in herein. Said process comprises of:

(i) Formation of a Corresponding Compound of Formula (I)

A compound of formula (I) may be obtained (Scheme 1) by starting from,for example, a compound of formula (II), wherein R^(X) may be F, OCH₃,OC(CH₃)₃, or OSiR′R″R′″ (wherein R′, R″ and R′″ are independently aryl(such as phenyl) or alkyl (such as methyl or tert-butyl)). If R^(X) is Fthe conversion into (I) may be carried out by for instance acidichydrolysis using aqueous HCl. If R^(X) is OCH₃ the conversion into (I)may be carried out by reaction with for instance trimethylsilyl iodidein a suitable solvent such as chloroform or by reaction with HBr in asuitable solvent such as acetic acid or by reaction with BBr₃ in asuitable solvent such as dichloromethane. If R^(X) is OC(CH₃)₃ theconversion into (I) may be carried out by reaction with for instancetrifluoroacetic acid in a suitable solvent such as dichloromethane. IfR^(X) is OSiR′R″R′″ the conversion into (I) may be carried out by forinstance HCl in a suitable solvent such as methanol or by usingtetrabutyl ammonium fluoride in tetrahydrofuran. If enantiomericallypure or enriched compound (II) is used in this reaction, anenantiomerically pure or enantiomerically enriched compound (I) isobtained.

Compounds of formula (II) are commercially available compounds, or areknown in the literature, or they are prepared by standard processesknown in the art. A compound of formula (I) or (II) may be separatedinto its enantiomers by standard processes known in the art by forexample chromatography on a chiral stationary phase.

General Methods

All solvents used were of analytical grade and commercially availableanhydrous solvents were routinely used for reactions. Starting materialswere available from commercial sources, or prepared according toliterature procedures. Room temperature refers to +20-25° C. Solventmixture compositions are given as volume percentages or volume ratios.Microwave heating was performed in a Biotage Initiator microwave cavityproducing continuous irradiation at 2.45 GHz. It is understood thatmicrowaves may be used for the heating of reaction mixtures.

Straight phase chromatography was manually performed on Merck Silica gel60 (0.040-0.063 mm), or automatically using an ISCO Combiflash®Companion™ system using SiliaSep™ normal-phase flash columns using thesolvent system indicated.

NMR spectra were recorded on a 400 MHz (or higher field) NMRspectrometer fitted with a probe of suitable configuration. Spectra wererecorded at ambient temperature unless otherwise stated. Chemical shiftsare given in ppm down- and upfield from TMS (0.00 ppm). The followingreference signals were used: the residual solvent signal of DMSO-d₆ δ2.5, CDCl₃ δ 7.26 or Methanol-d₄ δ 3.31. Resonance multiplicities aredenoted s, d, t, q, m and br for singlet, doublet, triplet, quartet,multiplet and broad, respectively.

High pressure liquid chromatography (HPLC) was performed on a reversephase column. A linear gradient was applied using for example mobilephase A (aqueous 0.1% NH₃ or aqueous 0.1% acetic acid or aqueous 0.1%formic acid) and B (acetonitrile or methanol). Mass spectrometer (MS)analyses were performed in positive ion mode using electrosprayionization (ES+). Preparative chromatography was run on a Gilson-PREPGX271 or GX281 with Trilution Ic as software on a reverse phase column.A linear gradient was applied using for example mobile phase A (aqueous0.1% NH₃ or aqueous 0.1% acetic acid or aqueous 0.1% formic acid) and B(acetonitrile or methanol).

Preparative chiral chromatography for separation of enantiomers was runon a Thar SFC using supercritical fluid chromatography on a chiralstationary phase. A linear gradient was applied using mobile phase A(carbon dioxide) and B (acetonitrile or methanol or ethanol or2-propanol or any mixtures thereof). Additives (such as diethyl amine orisopropyl amine or ammonia or formic acid or TFA) may be used.

Compounds have been named using BIOVIA Draw 16.1.

ABBREVIATIONS

-   Amphos (4-(N,N-Dimethylamino)phenyl)di-tert-butyl phosphine-   anh. anhydrous-   aq. aqueous-   BuLi butyl lithium-   DCM dichloromethane-   DMAc N,N-dimethyl acetamide-   DME 1,2-Dimethoxyethane-   DMF N,N-dimethyl formamide-   DMSO dimethyl sulfoxide-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   HPLC high pressure (or performance) liquid chromatography-   KOtBu potassium tert-butoxide-   LCMS liquid chromatography mass spectrometry-   MeCN acetonitrile-   2-MeTHF 2-methyl tetrahydrofuran-   MeOH methanol-   min. minute(s)-   NMR nuclear magnetic resonance-   Pd-118 Dichloro    [1,1′-bis(di-tertbutylphosphino)ferrocene]palladium(II)-   PEPPSI-iPr    1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene]3chloro-pyridyl)palladium(II)    dichloride-   Pd(OAc)₂ palladium(II) acetate-   PdCl₂(dppf)    [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloro-palladium(II)-   quant. quantitative-   rt room temperature-   sat. saturated-   TFA trifluoroacetic acid-   THF tetrahydrofuran

EXAMPLES Example 1 4-(2,6-Dichloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine

2,6-Dichloropyridine-4-carboxylic acid (2.88 g, 15 mmol) was taken up in1,4-Dioxane (75 ml) and oxalyl chloride (1.35 ml, 15.75 mmol) was added.The resulting mixture was stirred at 50° C. for 5 min then DMF (3 drop)was added and stirring continued for 45 min. When cooled to rt,PdCl₂(PPh₃)₂ (210 mg, 0.3 mmol), CuI (114 mg, 0.6 mmol),ethynyltrimethylsilane (2.12 ml, 15 mmol) and triethylamine (6.26 ml, 45mmol) were added and the mixture stirred at rt for 30 min.Phenylguanidinium nitrate (2.97 g, 15 mmol), K₂CO₃ (5.18 g, 37.5 mmol)and 2-ethoxyethan-1-ol (15 ml) were added and the resulting mixture wasrefluxed overnight. When cooled to rt the mixture was filtered through apad of silica gel eluted with DCM/MeOH/NH₃ (100:3:1) to give the productas a black gum. Recrystallization from MeOH gave the product as a solid(3.03 g, 64%). MS ES+ m/z 317 [M+H]⁺.

Example 24-(2-Tert-butoxy-6-chloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine

4-(2,6-Dichloropyridin-4-yl)-N-phenylpyrimidin-2-amine (3 g, 9.46 mmol),4 Å molecular sieves (3 g) and KOtBu (2.65 g, 23.65 mmol) were taken upin Toluene (50 ml) and the resulting mixture was stirred at 90° C. for 3h. When cooled to rt water (50 ml), aq. 2M HCl (20 ml) and EtOAc (50 ml)were added and the resulting precipitate was filtered off and discarded.The organic layer was separated and the aqueous layer extracted withEtOAc (2×25 ml). The combined organics were washed with brine, driedover Na₂SO₄, filtered and concentrated. The resulting residue was takenup in DCM (50 ml) together with active charcoal and the mixture wasstirred at rt for 15 min. Filtration through celite and concentration ofthe filtrate gave the product as a gum (1.5 g, 45%). MS ES+ m/z 355[M+H]⁺.

Example 34-[2-Tert-butoxy-6-(2-chlorophenyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

4-[2-(Tert-butoxy)-6-chloropyridin-4-yl]-N-phenylpyrimidin-2-amine (650mg, 1.13 mmol), (2-chlorophenyl)boronic acid (344 mg, 2.2 mmol), Pd-118(60 mg, 0.09 mmol) and K₂CO₃ (760 mg, 5.5 mmol) were taken up inDME:H₂O:EtOH (6:3:1, 15 ml) and the resulting mixture was stirred at 75°C. overnight. More (2-chlorophenyl)boronic acid (344 mg, 2.2 mmol) andPd-118 (60 mg, 0.09 mmol) were added and the mixture stirred at 75° C.for 4 h. When cooled to rt the mixture was concentrated and theresulting residue was taken up in water (20 ml) and EtOAc (50 ml). Themixture was stirred at rt for 10 min and then filtered. To the filtratewas added EtOAc (20 ml) and the organic layer separated. The aqueouslayer was extracted with EtOAc (2×10 ml) and the combined organics werewashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified on a silica gel column eluted with 0-50% EtOAc in Heptane,followed by preparative HPLC to give the product as a solid (140 mg,18%). MS ES+ m/z 431 [M+H]⁺.

Example 44-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one

TFA (0.1 ml, 1.35 mmol) was added to a solution of4-[2-(tert-butoxy)-6-(2-chlorophenyl)pyridin-4-yl]-N-phenylpyrimidin-2-amine(130 mg, 0.3 mmol) in DCM (8 ml) at rt and the resulting mixture wasstirred at rt for 2 h. More TFA (0.1 ml, 1.35 mmol) was added andstirring continued for 2 h. The mixture was concentrated and theresulting residue was taken up in MeOH (10 ml). NH₄OH (28%, 3 ml) wasadded and the mixture stirred at rt for 1 h. The precipitate wasfiltered off, washed with water, MeOH and dried. The solid was dissolvedin boiling pyridine (15 ml) and allowed to cool to rt. To the cloudysolution was added MeOH (10 ml), with stirring, and after 10 min at rtthe mixture was cooled in refrigerator for 15 min. The resultingprecipitate was filtered off, washed sequentially with MeOH and Pentaneand dried to give the product as a solid (30 mg, 25%). ¹H NMR (500 MHz,DMSO-d6) δ ppm 12.15 (s, 1H), 9.77 (s, 1H), 8.62 (d, 1H), 7.79 (d, 2H),7.69-7.56 (m, 2H), 7.51 (dq, 2H), 7.30 (q, 2H), 7.18 (s, 1H), 6.97 (t,1H). MS ES+ m/z 375 [M+H]⁺.

Example 54-[2-Tert-butoxy-6-(3-pyridyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

The title compound was prepared as described in Example 3, using(pyridin-3-yl)boronic acid, to give the product (435 mg, 97%). MS ES+m/z 398 [M+H]⁺.

Example 6 4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one

The title compound was prepared as described in Example 4,recrystallized from 2-propanol, to give the product as a solid (14 mg,14%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 12.08 (s, 1H), 9.81 (s, 1H), 9.14(s, 1H), 8.72-8.58 (m, 2H), 8.31 (d, 1H), 7.82 (d, 2H), 7.68-7.51 (m,3H), 7.38-7.27 (m, 3H), 6.99 (t, 1H). MS ES+ m/z 342 [M+H]⁺.

Example 74-[2-Tert-butoxy-6-(4-pyridyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

The title compound was prepared as described in Example 3, using(pyridin-4-yl)boronic acid, to give the product (100 mg, 64%). MS ES+m/z 398 [M+H]⁺.

Example 8 4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one

The title compound was prepared as described in Example 4,recrystallized from 2-propanol, to give the product as a solid (20 mg,21%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 11.85 (s, 1H), 9.83 (s, 1H), 8.76(d, 2H), 8.67 (d, 1H), 7.98 (s, 2H), 7.82 (d, 2H), 7.62 (d, 1H),7.44-7.24 (m, 3H), 7.00 (t, 1H). MS ES+ m/z 342 [M+H]⁺.

Example 94-(2-Tert-butoxy-6-morpholino-4-pyridyl)-N-phenyl-pyrimidin-2-amine

4-(2-Tert-butoxy-6-chloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine (190 mg,0.54 mmol), Pd(OAc)₂ (8 mg, 0.04 mmol) and XantPhos (19 mg, 0.03 mmol)were dissolved in Toluene (6 ml). Morpholine (185 μl, 2.14 mmol) andKOtBu (180 mg, 1.61 mmol) were added and the resulting mixture wasstirred at 100° C. overnight. When cooled to rt, EtOAc and brine wereadded, the organic layer separated and the aqueous layer extracted withEtOAc. The combined organics were washed with brine, dried over MgSO₄,filtered, concentrated and purified on a silica gel column eluted with20% EtOAc in Heptane to give the product (60 mg, 28%). MS ES+ m/z 406[M+H]⁺.

Example 10 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one

The title compound was prepared as described in Example 4 to give theproduct as a solid (26 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.33(s, 1H) 3.47 (br. s., 4H) 3.65-3.79 (m, 4H) 6.62 (s, 1H) 6.85 (br. s.,1H) 6.97 (t, 1H) 7.31 (t, 2H) 7.42 (s, 1H) 7.82 (d, 2H) 8.58 (d, 1H)9.72 (s, 1H). MS ES+ m/z 350 [M+H]⁺.

Example 11 4-Benzyloxy-2,6-dichloro-pyridine

60% NaH (945 mg, 24.7 mmol) was added portion wise to a solution of2,4,6-trichloropyridine (4.5 g, 24.7 mmol) in DMF (25 ml) at 0° C. After20 min phenylmethanol (2.7 g, 24.7 mmol) was added dropwise and themixture was stirred for 3 h. Water (30 ml) was added and the precipitatewas filtered off. The solid was dissolved in EtOAc, dried over MgSO₄,filtered and concentrated to give the product as a solid (5 g, 80%). MSES+ m/z 254 [M+H]⁺.

Example 12 4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine

4-Benzyloxy-2,6-dichloro-pyridine (5 g, 19.7 mmol) and KOtBu (2.2 g,19.7 mmol) were dissolved in dry 2-MeTHF (25 ml) and the mixture wasstirred at 70° C. for 2 h. When cooled to rt the mixture was filtered,concentrated and purified on a silica gel column eluted with 30% EtOAcin Heptane to give the product (4 g, 70%). MS ES+ m/z 292 [M+H]⁺.

Example 134-Benzyloxy-2-tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridine

4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine (4 g, 13.7 mmol),2-(trifluoromethyl)piperidine (2.3 g, 15.1 mmol), PEPPSI-iPr (146 mg,1.37 mmol) and KOtBu (3.85 g, 34.3 mmol) were taken up in 1,4-Dioxane(30 ml) and the mixture was stirred at 90° C. for 2 h. When cooled to rtwater and EtOAc were added and the organic layer separated, filtered,concentrated and purified on silica gel column eluted with 30% EtOAc inHeptane to give the product (4.1 g, 73%). MS ES+ m/z 409 [M+H]⁺.

Example 14 2-Tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridin-4-ol

A mixture of4-benzyloxy-2-tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridine(3.5 g, 8.57 mmol) and 10% Pd/C (600 mg, 0.56 mmol) in MeOH and EtOAcwas hydrogenated (1.5 bar) at rt for 2 h. The mixture was filteredthrough celite and concentrated to give the product (2.7 g, quant.). MSES+ m/z 319 [M+H]⁺.

Example 15[2-Tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]-4-pyridyl]trifluoromethanesulfonate

2-Tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridin-4-ol (2.7 g,8.48 mmol) and Et₃N (1.66 ml, 11.9 mmol) was taken up in DCM (20 mL) at0° C. Trifluoromethylsulfonyl trifluoromethanesulfonate (2.54 ml, 11.9mmol) was added dropwise over 5 minutes and stirred for 1 h. The mixturewas washed with sat. aq. NaHCO₃ (2×20 mL), concentrated and purified onsilica gel column eluted with 20% EtOAc in Heptane to give the product(3.5 g, 92%). MS ES+ m/z 451 [M+H]⁺.

Example 162-Tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)-1-piperidyl]pyridine

4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.96 g, 11.7 mmol),[2-tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]-4-pyridyl]trifluoromethanesulfonate (3.5 g, 7.77 mmol), KOAc (1.14 g, 11.7 mmol)and PdCl₂(dppf) (215 mg, 0.29 mmol) were taken up in Toluene (10 ml) andstirred at 90° C. for 5 h. When cooled to rt the mixture wasconcentrated and the residue dissolved in EtOAc, washed with water,concentrated and purified on silica gel column eluted with 0-60% EtOAcin Heptane to give the product (2.15 g, 65%). MS ES+ m/z 347 [M+H]⁺.

Example 17 N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine

2-Bromo-4-chloro-pyridine (250 mg, 1.25 mmol), 2-methylpyrimidin-4-amine(107 mg, 0.9 mmol), PdCl₂(dppf) (14 mg, 0.015 mmol) and dppf (43 mg,0.07 mmol) were taken up in Toluene. 1M KOtBu (167 mg, 1.4 mmol) in THFwas added and the resulting mixture stirred at 110° C. overnight. Workup and purification on a silica gel column chromatography gave theproduct as a solid (100 mg, 36%). MS ES+ m/z 221 [M+H]⁺.

Example 184-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one

1-[3-Tert-butoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)piperidine(100 mg, 0.23 mmol), K₂CO₃ (81 mg, 0.59 mmol),N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (52 mg, 0.23 mmol) andPdCl₂(dppf) (15 mg, 0.02 mmol) were dissolved in 1,4-Dioxane (3 ml) andwater (1 ml) and the resulting mixture was stirred at 90° C. for 2 h.When cooled to rt water and EtOAc were added and the organic layerseparated and concentrated. The residue was dissolved in DCM (3 ml), TFA(0.5 ml, 6.7 mmol) was added and the mixture stirred at rt for 30 min.The mixture was concentrated, dissolved in MeOH, filtered and purifiedby preparative HPLC to give the product as a solid (7 mg, 6%). ¹H NMR(500 MHz, METHANOL-d4) δ ppm 1.17-1.33 (m, 1H), 1.54-1.66 (m, 1H),1.68-1.77 (m, 2H), 1.81 (br d, 3H), 2.08 (br d, 1H), 2.57 (s, 3H),3.15-3.29 (m, 1H), 3.86 (br d, 1H), 5.16 (br s, 1H), 6.21-6.27 (m, 2H),7.17 (dd, 1H), 7.38 (d, 1H), 8.07 (br s, 1H), 8.23 (d, 1H), 8.32 (d,1H). MS ES+ m/z 431 [M+H]⁺.

Example 19 2-Anilino-1H-pyrimidin-6-one

2-Methylsulfanyl-1H-pyrimidin-6-one (5 g, 35.21 mmol) and aniline (3.2g, 35.21 mmol) were taken up in Diglyme (50 ml) and the resultingmixture was stirred at 170° C. for 5 h. When cooled to rt water wasadded and the formed precipitate was filtered off, washed with water anddried to give the product as a solid (3 g, 46%). MS ES+ m/z 188 [M+H]⁺.

Example 20 4-chloro-N-phenyl-pyrimidin-2-amine

PCl₅ (1 g, 5.34 mmol) was added portion wise to a solution of2-Anilino-1H-pyrimidin-6-one (1.5 g, 5.34 mmol) in POCl₃ (5 ml) and theresulting mixture was stirred at 110° C. overnight. When cooled to rtice/water were added and the mixture extracted with EtOAc. The combinedorganics were dried over Na₂SO₄, filtered, concentrated and purified ona silica gel column to give the product as a solid (840 mg, 76%). MS ES+m/z 206 [M+H]⁺.

Example 214-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using4-chloro-N-phenyl-pyrimidin-2-amine, to give the product as a solid (11mg, 8%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.52 (br s, 1H), 1.70 (br s,2H), 1.78 (br d, 2H), 2.02 (br d, 1H), 3.09 (br t, 1H), 4.22 (br s, 1H),5.54 (br s, 1 H), 6.65 (s, 1H), 6.95-7.04 (m, 2H), 7.31 (t, 2H), 7.44(d, 1H), 7.83 (d, 2H), 8.60 (d, 1H), 9.72 (s, 1H), 10.47 (br s, 1H). MSES+ m/z 416 [M+H]⁺.

Example 224-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-3-(trifluoromethyl)morpholine

The title compound was prepared as described in Example 13, using3-(trifluoromethyl)morpholine, to give the product as an oil (1 g, 50%).MS ES+m/z 411 [M+H]⁺.

Example 232-tert-Butoxy-6-[3-(trifluoromethyl)morpholin-4-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give theproduct (780 mg, 99%). MS ES+ m/z 321 [M+H]⁺.

Example 24[2-tert-Butoxy-6-[3-(trifluoromethyl)morpholin-4-yl]-4-pyridyl]trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give theproduct as an oil (800 mg, 81%). MS ES+ m/z 453 [M+H]⁺.

Example 254-[6-tert-Bbutoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholine

The title compound was prepared as described in Example 16 to give theproduct (270 mg, 33%). MS ES+ m/z 431 [M+H]⁺.

Example 264-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholine,to give the product as a solid (6 mg, 6%). ¹H NMR (500 MHz, METHANOL-d₄)δ ppm 2.52-2.62 (m, 3H), 3.50-3.69 (m, 2H), 3.70-3.85 (m, 2H), 4.04 (dd,1H), 4.30 (d, 1H), 5.05-5.19 (m, 1H), 6.34 (m, 2H), 7.20 (dd, 1H), 7.45(d, 1H), 8.04 (s, 1H), 8.25 (d, 1H), 8.30-8.40 (m, 1H). MS ES+ m/z 433[M+H]⁺.

Example 274-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholineand 4-chloro-N-phenyl-pyrimidin-2-amine, to give the product as a solid(15 mg, 17%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.33-3.38 (m, 1H),3.53-3.59 (m, 1H), 3.77 (br d, 1H), 4.00 (br dd, 2H), 4.21 (d, 1H), 5.29(br dd, 1H), 6.71 (s, 1H), 6.96 (s, 1H), 6.98-7.01 (m, 1H), 7.32 (t,2H), 7.43 (d, 1H), 7.84 (d, 2H), 8.61 (d, 1H), 9.72 (s, 1H), 10.33-10.82(m, 1H). MS ES+ m/z 418 [M+H]⁺.

Example 281-[(4-Fluorophenyl)methylsulfonyl]-3-(trifluoromethyl)piperazine

2-(Trifluoromethyl)-piperazine (2 g, 13 mmol) and TEA (2.17 ml, 15.6mmol) were dissolved in DCM (30 ml). (4-fluorophenyl)methanesulfonylchloride (2.71 g, 13 mmol) was added in small portions at 0° C. and themixture was stirred at rt overnight. Water (45 ml) was added and themixture extracted with DCM (2×80 ml). The combined organics were washedtwice with brine, dried over Na₂SO₄, filtered and concentrated to givethe product as a solid (3.5 g, 83%). MS ES+ m/z 327 [M+H]⁺.

Example 291-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazine

A mixture of1-[(4-fluorophenyl)methylsulfonyl]-3-(trifluoromethyl)piperazine (1.2 g,3.68 mmol), 4-benzyloxy-2-tert-butoxy-6-chloro-pyridine (1.34 g, 4.6mmol), Cs₂CO₃ (2.4 g, 7.35 mmol), XantPhos (206 mg, 0.37 mmol) andPd(OAc)₂ (83 mg, 0.37 mmol) in anh. degassed 1,4-dioxane (50 ml) wasrefluxed overnight under argon. Water was added and the mixtureextracted with EtOAc. The combined organics were dried over Na₂SO₄,filtered, concentrated and purified on a silica gel column, eluted with0-100% EtOAc in Heptane, to give the product (1.25 g, 58%). MS ES+ m/z582 [M+H]⁺.

Example 302-tert-Butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give theproduct (1.22 g, 96%). MS ES+ m/z 492 [M+H]⁺.

Example 31[2-tert-Butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give theproduct (700 mg, 45%). MS ES+ m/z 624 [M+H]⁺.

Example 321-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 16 to give theproduct (490 mg, 73%). MS ES+ m/z 602 [M+H]⁺.

Example 336-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using1-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazine,to give the product as a solid (14 mg, 14%). ¹H NMR (500 MHz, DMSO-d6) δppm 2.85-2.94 (m, 1H), 3.15 (br d, 1H), 3.13-3.14 (m, 1H), 3.17-3.18 (m,1H), 3.22 (br t, 1H), 3.27-3.31 (m, 1H), 3.62 (br d, 1H), 3.89 (br d,1H), 4.33 (br d, 1H), 4.52 (s, 2H), 5.57 (br s, 1H), 6.31 (s, 1H), 6.65(br s, 1H), 7.24 (t, 2H), 7.32 (dd, 1H), 7.48 (dd, 2H), 7.62 (br d, 1H),8.04 (s, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 10.23 (s, 1H). MS ES+ m/z 604[M+H]⁺.

Example 34 1-Ethylsulfonyl-3-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 28, usingethanesulfonyl chloride, to give the product as a solid (3 g, 98%). MSES+m/z 247 [M+H]⁺.

Example 351-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-4-ethylsulfonyl-2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 29, using1-ethylsulfonyl-3-(trifluoromethyl)piperazine, to give the product as asolid (2.53 g, 67%). MS ES+ m/z 502 [M+H]⁺.

Example 362-tert-Butoxy-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give theproduct (1.94 g, 85%). MS ES+ m/z 412 [M+H]⁺.

Example 37[2-tert-Butoxy-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give theproduct (1.56 g, 62%). MS ES+ m/z 544 [M+H]⁺.

Example 381-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-ethylsulfonyl-2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 16 to give theproduct (1.2 g, 86%). MS ES+ m/z 440 [M+H]⁺ (boronic acid).

Example 396-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using1-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-ethylsulfonyl-2-(trifluoromethyl)piperazine,to give the product as a solid (7 mg, 7%). ¹H NMR (500 MHz, DMSO-d6) δppm 1.24 (t, 3H), 2.50 (br s, 3H), 2.97-3.05 (m, 1H), 3.13 (q, 2H),3.23-3.30 (m, 2H), 3.67 (br d, 1H), 3.95 (br d, 1H), 4.36 (br d, 1H),5.63 (br s, 1H), 6.31 (s, 1H), 6.67 (s, 1H), 7.33 (dd, 1H), 7.63 (d,1H), 8.04 (s, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 10.23 (s, 1H), 10.66 (brs, 1H). MS ES+ m/z 524 [M+H]⁺.

Example 404-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholineand N-(4-chloro-2-pyridyl)oxazol-2-amine (Tetrahedron Letters (2012),53, (24), 3038-3043), to give the product as a solid (5 mg, 5%). ¹H NMR(500 MHz, DMSO-d6) δ ppm 3.23-3.31 (m, 1H), 3.40-3.57 (m, 1H), 3.75 (brd, 1H), 3.94-4.04 (m, 2H), 4.19 (d, 1H), 5.28-5.35 (m, 1H), 6.27 (s,1H), 6.57 (s, 1H), 7.05-7.10 (m, 1H), 7.29 (br d, 1H), 7.73 (s, 1H),8.28-8.35 (m, 2H), 10.84 (br s, 2H). MS ES+ m/z 408 [M+H]⁺.

Example 41 N-(4-chloro-2-pyridyl)-2-methyl-thiazol-4-amine

A mixture of 4-bromo-2-methyl-thiazole (1.5 g, 8.52 mmol),4-chloropyridin-2-amine (1.3 g, 10.22 mmol) and Cs₂CO₃ (6.92 g, 21.3mmol) in 1,4 dioxane (30 ml) was degassed with nitrogen for 20 min.Pd₂(dba)₃ (0.389 g, 0.42 mmol) and Xantphos (0.24 g, 0.42 mmol) wereadded and the resulting mixture was stirred at 90° C. for 16 h. Whencooled to rt the mixture was filtered through celite, concentrated andpurified by preparative HPLC to give the product as a solid (600 mg,31%). ¹H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.15 (d, 1H), 7.37 (s,1H), 7.03 (d, 1H), 6.85-6.84 (m, 1H), 2.61 (s, 3H). MS ES+ m/z 226[M+H]⁺.

Example 424-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholineand N-(4-chloro-2-pyridyl)-2-methyl-thiazol-4-amine, to give the productas a solid (20 mg, 21%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.62-2.65 (m,3H), 3.32 (br s, 1H), 3.54 (td, 1H), 3.71-3.80 (m, 1H), 3.93-4.05 (m,2H), 4.20 (d, 1H), 5.30 (br dd, 1H), 6.22 (s, 1H), 6.53 (s, 1H), 7.08(dd, 1H), 7.23 (s, 1H), 7.43 (s, 1H), 8.27 (d, 1H), 10.00 (s, 1H), 10.57(br s, 1H). MS ES+ m/z 438 [M+H]⁺.

Example 434-Benzyloxy-2-tert-butoxy-6-[2-(trifluoromethyl)phenyl]pyridine

4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine (1.46 g, 5 mmol),[2-(trifluoromethyl)phenyl]boronic acid (950 mg, 5 mmol), K₂CO₃ (1.73 g,12.5 mmol) and PdCl₂(dppf) (366 mg, 0.5 mmol) were dissolved in1,4-dioxane (25 ml) and water (5 ml) and the resulting mixture wasstirred at 90° C. for 2 h. When cooled to rt the mixture was dilutedwith water and EtOAc. The organic layer was separated and the aqueouslayer extracted with EtOAc. The combined organics were filtered throughcelite, dried over Na₂SO₄, filtered, concentrated and purified on asilica gel column eluted with 0-80% EtOAc in heptane to give the productas a solid (1.58 g, 79%). MS ES+ m/z 402 [M+H]⁺.

Example 44 2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give theproduct (948 mg, 72%). MS ES+ m/z 312 [M+H]⁺.

Example 45 [2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give theproduct (720 mg, 54%). MS ES+ m/z 388 [M-tBu]⁺.

Example 462-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)phenyl]pyridine

The title compound was prepared as described in Example 16 to give theproduct (450 mg, 76%). MS ES+ m/z 340 [M+H]+(boronic acid).

Example 474-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18, using2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)phenyl]pyridine,to give the product as a solid (10 mg, 9%). ¹H NMR (500 MHz, DMSO-d6) δppm 2.47 (s, 3H), 6.46-6.63 (m, 1H), 6.76-6.82 (m, 1H), 7.30-7.37 (m,1H), 7.58-7.64 (m, 1H), 7.65-7.68 (m, 1H), 7.71-7.76 (m, 1H), 7.78-7.84(m, 1H), 7.88-7.93 (m, 1H), 8.03-8.10 (m, 1H), 8.32-8.44 (m, 2H),10.18-10.31 (m, 1H), 11.25-11.87 (m, 1H). MS ES+ m/z 424 [M+H]⁺.

Example 48 4-Chloro-N-(2-methylpyrazol-3-yl)pyridin-2-amine

The title compound was prepared as described in Example 41, using2-methylpyrazol-3-amine and 2-bromo-4-chloro-pyridine. Purification on asilica gel column eluted with 0-5% MeOH in DCM gave the product as asolid (1.2 g, quant.). MS ES+ m/z 209 [M+H]⁺.

Example 494-[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(2-methylpyrazol-3-yl)pyridin-2-amine

A mixture of 4-chloro-N-(2-methylpyrazol-3-yl)pyridin-2-amine (58 mg,0.28 mmol),2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)phenyl]pyridine(117 mg, 0.28 mmol), K₂CO₃ (77 mg, 0.56 mmol) and PdCl₂(dppf) (20 mg,0.03 mmol) in 1,4-dioxane (2 ml) and water (0.5 ml) was heated andstirred at 90° C. for 6 h. When cooled to rt the mixture was dilutedwith water and EtOAc. The organic layer was separated, and the aqueouslayer extracted with EtOAc. The combined organics were washed withbrine, dried over Na₂SO₄, filtered, concentrated and purified on asilica gel column eluted with 0-6% MeOH in DCM to give the product as asolid (94 mg, 51% yield, 70% purity). MS ES+ m/z 468 [M+H]⁺.

Example 504-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

TFA (1.05 ml, 14.1 mmol) was added to a solution of4-[2-tert-butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(2-methylpyrazol-3-yl)pyridin-2-amine(94 mg, 0.14 mmol, 70%) in DCM (7 ml) at 0° C. and the resulting mixturewas stirred at 0° C. for 1 h. The mixture was concentrated, chased withtoluene and purified by preparative HPLC to give the product as a solid(11 mg, 19%). ¹H NMR (500 MHz, DMSO-d6) δ ppm 3.68 (s, 3H), 6.28 (d,1H), 6.51 (br s, 1H), 6.72 (d, 1H), 7.02-7.11 (m, 2H), 7.34 (d, 1H),7.65 (d, 1H), 7.71-7.82 (m, 2H), 7.89 (d, 1H), 8.20 (d, 1H), 8.93 (s,1H), 12.03 (br s, 1H). MS ES+m/z 412 [M+H]⁺.

Example 51N-[4-[2-tert-butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-2-pyridyl]-2-methyl-thiazol-4-amine

The title compound was prepared as described in Example 49, usingN-(4-chloro-2-pyridyl)-2-methyl-thiazol-4-amine, to give the product asa solid (145 mg, 60% yield, 80% purity). MS ES+ m/z 485 [M+H]⁺.

Example 524-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, to give theproduct as a solid (45 mg, 43%). ¹H NMR (500 MHz, DMSO-d6) δ ppm2.53-2.65 (m, 3H), 6.48 (br s, 1H), 6.63-6.79 (m, 1H), 7.08 (dd, 1H),7.26 (s, 1H), 7.43 (s, 1H), 7.66 (d, 1H), 7.72-7.83 (m, 2H), 7.90 (d,1H), 8.28 (d, 1H), 10.05 (s, 1H), 12.02 (br s, 1H). MS ES+ m/z 429[M+H]⁺.

Example 53N-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amine

A mixture of N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (1.08 g,4.89 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.55 g, 6.12 mmol), KOAc (961 mg, 9.79 mmol) and PdCl₂(dppf) (358 mg,0.49 mmol) in 1,4-dioxane (25 ml) was stirred at 100° C. overnight. Whencooled to rt, 2-tert-butoxy-6-chloro-4-iodo-pyridine (Bioorganic &Medicinal Chemistry Letters (2012), 22, (5), 1940-1943, 1.53 g, 4.89mmol), K₂CO₃ (1.35 g, 9.79 mmol), PdCl₂(dppf) (179 mg, 0.25 mmol) andwater (6 ml) were added and the reaction was heated and stirred 85° C.for 2 h. When cooled to rt, water (25 ml) was added and the mixture wasextracted with EtOAc. The combined organics were dried over Na₂SO₄,filtered, concentrated and purified on a silica gel column eluted with25-100% EtOAc in heptane to give the product as a solid (1.61 g, 80%yield, 90% purity). MS ES+ m/z 370 [M+H]⁺.

Example 54N-[4-[2-tert-butoxy-6-(4-methyl-3-pyridyl)-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4-amine

The title compound was prepared as described in Example 49, usingN-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amineand (4-methyl-3-pyridyl)boronic acid (1.5 eq), to give the product as asolid (75 mg, 70%). MS ES+ m/z 427 [M+H]⁺.

Example 556-(4-Methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, to give theproduct as a solid (55 mg, 58%). ¹H NMR (500 MHz, DMSO-d6) δ ppm2.36-2.41 (m, 3H), 2.48-2.50 (m, 3H), 6.62 (br s, 1H), 6.74 (br s, 1H),7.37-7.42 (m, 2H), 7.68 (d, 1H), 8.05 (s, 1H), 8.36 (d, 1H), 8.40 (d,1H), 8.54 (d, 1H), 8.57 (s, 1H), 10.26 (s, 1H), 12.06 (br s, 1H). MS ES+m/z 371 [M+H]⁺.

Example 56N-[4-[2-tert-butoxy-6-[2-(trifluoromethyl)-3-pyridyl]-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4-amine

The title compound was prepared as described in Example 49, usingN-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amineand [2-(trifluoromethyl)-3-pyridyl]boronic acid (1.5 eq), to give theproduct as a solid (110 mg, 92%). MS ES+ m/z 481 [M+H]⁺.

Example 574-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, to give theproduct as a solid (50 mg, 54%). ¹H NMR (500 MHz, DMSO-d6) δ ppm2.46-2.49 (m, 3H), 6.68 (br s, 1H), 6.83 (br s, 1H), 7.35 (dd, 1H), 7.62(d, 1H), 7.87 (dd, 1H), 8.07 (s, 1H), 8.19 (d, 1H), 8.36 (d, 1H), 8.41(d, 1H), 8.88 (d, 1H), 10.29 (s, 1H), 11.71-12.58 (m, 1H). MS ES+ m/z425 [M+H]⁺.

Example 58N-[4-[2-tert-butoxy-6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4-amine

The title compound was prepared as described in Example 49, usingN-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amineand 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]boronic acid (1.2 eq), togive the product as a solid (194 mg, 66%). MS ES+ m/z 498 [M+H]⁺.

Example 596-[1-Ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, to give theproduct as a solid (2 mg, 1%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42-1.46(m, 3H), 2.48-2.49 (m, 3H), 4.24-4.31 (m, 2H), 6.65-6.67 (m, 1H),6.66-6.74 (m, 1H), 7.26-7.31 (m, 1H), 7.61-7.67 (m, 1H), 7.97-8.02 (m,1H), 8.35 (d, 1H), 8.38-8.41 (m, 1H), 8.41-8.45 (m, 1H), 8.43-8.43 (m,1H), 10.31-10.36 (m, 1H). MS ES+ m/z 442 [M+H]⁺.

Example 60 4-Chloro-N-(1-methylimidazol-4-yl)pyridin-2-amine

The title compound was prepared as described in Example 41, using1-methylimidazol-4-amine and 2,4-dichloropyridine and heating themixture in a microwave reactor at 160° C. for 1 h, to give the productas a solid (0.1 g, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.59(s, 1H), 8.17 (d, 1H), 7.48 (s, 1H), 6.98-6.95 (m, 2H), 3.80 (s, 3H). MSES+ m/z 209 [M+H]⁺.

Example 614-[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(1-methylimidazol-4-yl)pyridin-2-amine

The title compound was prepared as described in Example 49, using4-chloro-N-(1-methylimidazol-4-yl)pyridin-2-amine, to give the productas a solid (50 mg, 21% yield, 80% purity). MS ES+ m/z 468 [M+H]⁺.

Example 624-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, to give theproduct as a solid (18 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.63(s, 3H), 6.28-6.56 (m, 1H), 6.67 (br s, 1H), 6.93 (d, 1H), 7.18 (s, 1H),7.28 (d, 1H), 7.35 (s, 1H), 7.65 (d, 1H), 7.70-7.82 (m, 2H), 7.89 (d,1H), 8.20 (d, 1H), 9.27 (s, 1H), 11.44-12.43 (m, 1H). MS ES+ m/z 412[M+H]⁺.

Example 63 6-(2-Chlorophenyl)-4-hydroxy-1H-pyridin-2-one

Ethyl 3-oxobutanoate (6.33 ml, 50 mmol) was added dropwise to asuspension of 60% NaH (1.92 g, 50 mmol) in 2-MeTHF (60 ml) at −78° C.under a nitrogen atmosphere. After 5 min the cooling bath was removedand the mixture was stirred at rt for 20 min. The mixture was cooledback to −78° C. and 1.6 M n-BuLi (31.25 ml, 50 mmol) was added slowlyover 20 min. The resulting solution was stirred at −78° C. for 30 min.2-Chlorobenzonitrile (6.88 g, 50 mmol) was added as a solid in oneportion and the reaction mixture was stirred on the thawing cooling bathovernight. The mixture was cooled to 0° C. and MeOH (15 ml) was addedslowly. The cooling bath was removed and the mixture stirred at rt for30 min and then cooled to 0° C. again. The mixture was neutralized byslow addition of conc. HCl and the resulting precipitate was filteredoff, washed with EtOH, pentane and dried to give the product as a solid(11.08 g, 87%). MS ES+ m/z 222 [M+H]⁺.

Example 64 2,4-Dichloro-6-(2-chlorophenyl)pyridine

6-(2-Chlorophenyl)-4-hydroxy-1H-pyridin-2-one (5 g, 22.56 mmol) wastaken up in POCl₃ (40 ml) and N,N-dimethylaniline (5.5 ml, 43.4 mmol)was added slowly. The resulting mixture was refluxed overnight. Whencooled to rt the mixture was poured onto ice (600 ml) and stirred at rtfor 30 min. The precipitate was filtered off and washed with water. Thesolid was dissolved in EtOAc (100 ml), dried over Na₂SO₄, filtered andconcentrated to give the product as a solid (7 g, 83%). MS ES+ m/z 258[M+H]⁺.

Example 65 4-Chloro-6-(2-chlorophenyl)-1H-pyridin-2-one

2,4-Dichloro-6-(2-chlorophenyl)pyridine (5.7 g, 22.05 mmol) and KOtBu(6.19 g, 55.12 mmol) were taken up in toluene (75 ml) and the resultingmixture was stirred at 100° C. for 2 h. When cooled to rt, water (40 ml)was added and the organic layer separated. The aqueous layer was madeslightly acidic using conc. HCl and extracted with EtOAc (2×40 ml). Thecombined organics were washed with brine (50 ml), dried over Na₂SO₄,filtered and concentrated. The resulting residue was taken up in DCM (30ml) and TFA (5 ml, 67.3 mmol) was added. The reaction mixture wasstirred at rt for 1 h, concentrated and the resulting residue was takenup in MeOH (25 ml). 30% NH₄OH (20 ml) and water (20 ml) were added andthe mixture was stirred at rt overnight. The formed precipitate wasfiltered off, washed with water, EtOH, pentane and dried to give theproduct a solid (4.13 g, 78%). MS ES+ m/z 240 [M+H]⁺.

Example 666-(2-Chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

A mixture of N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (132 mg,0.6 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(190 mg, 0.75 mmol) and PdCl₂(dppf) (22 mg, 0.06 mmol) in 1,4-dioxane(1.5 ml) was stirred in a sealed tube at 100° C. for 15 h. When cooledto rt, 4-chloro-6-(2-chlorophenyl)-1H-pyridin-2-one (144 mg, 0.6 mmol),K₂CO₃ (83 mg, 0.6 mmol), PdCl₂(dppf) (11 mg, 0.03 mmol), 1,4-dioxane (1ml) and water (0.5 ml) were added and the resulting mixture was flushedwith argon, heated and stirred at 85° C. for 2 h. When cooled to rt,water (25 ml) was added and the mixture was extracted with DCM. Thecombined organics were dried over Na₂SO₄, filtered, concentrated andpurified by preparative HPLC to give the product as a solid (20 mg, 9%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.48-2.50 (m, 3H), 6.66 (br s, 1H), 6.74(s, 1H), 7.37 (dd, 1H), 7.46-7.56 (m, 2H), 7.59-7.68 (m, 3H), 8.05 (s,1H), 8.36 (d, 1H), 8.40 (d, 1H), 10.27 (s, 1H), 11.57-12.34 (m, 1H). MSES+m/z 390 [M+H]⁺.

Example 67

The following compound is synthesized using suitable changes of startingmaterial, and if necessary customizations of reaction conditions and thelike.

-   6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one.

Example 68

Vps34 Biochemical Assay

Dilution series of compounds of the invention were prepared in DMSO at100 times the final assay concentration (n₁=n₀/3 in 10 points). Thecompounds were further diluted to 4 times the assay concentration inassay buffer (Life technologies buffer Q, PV5125, diluted 5 timessupplemented with 2 mM DTT and 2 mM MnCl₂). 2.5 μl of the dilutedcompounds were added to a 384 well assay plate followed by 2.5 μl of16.5 nM Vps34 enzyme (Life technologies, PV5126). Enzyme and compoundswere pre-incubated at rt for 15 min. Then 5 μl of substrate mixcontaining 20 μM ATP (Life technologies, PV3227) and 200 μM PI:PSsubstrate (Life technologies, PV5122) in assay buffer was added to thewells containing compound and enzyme. Mixing was performed by pipettingseveral times. The reaction was incubated at room temperature for 1 h.Then 5 μl stop-detection mix, prepared as described in the Adapta kinaseassay kit instructions (Life technologies, PV5099) containing AdaptaEu-anti-ADP antibody (2.3 nM), Alexa Fluor 647 ADP tracer (9 nM) andEDTA (30 mM) in TR-FRET buffer, was added to quench the reaction. Mixingwas performed by pipetting several times. The assay plate was thenincubated at room temperature for 30 min and read with Artemis microplate reader. Percent inhibition of the compounds as compared to DMSOtreated control samples was calculated. By the use of Dotmatics softwarecompound concentration versus percent inhibition was fitted to generateIC₅₀ values. The example compounds effectively inhibited Vps34 and theresults of the assay are shown in Table 1 (Median IC₅₀ nM Adapta).

TABLE 1 Median IC₅₀ values for the Vps34 assay Example Compound MedianIC₅₀ nM Adapta 4 <5 6 <5 8 6 10 <5 18 <5 21 <5 26 <5 27 <5 33 <5 39 <540 <5 42 13 47 <5 50 55 52 52 55 <5 57 <5 59 <5 62 12 66 <5

Example 69

High Content Screening Autophagy Assay

Human osteosarcoma cells (HOS) stably expressing a Green FluorescentProtein (GFP) tagged LC3 (GFP-LC3) were used to determine the inhibitoryeffect on autophagy of proprietary compounds. For that purpose,autophagy was activated by using the mTOR inhibitor KU-0063794 at 500 nMin the presence of Bafilomycin A1 (Sigma-Aldrich) at 5 nM. Shortly,cells were plated overnight in clear bottom 96-well plates in DMEM—HighModified media (Hi-Clone Cat #SH30285.01). At the start of theexperiment, the media was removed and replaced with fresh mediacontaining the mTOR inhibitor, Bafilomycin A1 and the vehicle or a testcompound as indicated. After 6 hours the media was removed, cells werewashed twice with ice-cold phosphate buffered saline (PBS) and fixedwith 4% paraformaldehyde for 20 minutes at room temperature. Then thecells were washed twice with ice-cold PBS before adding Hoechst 33342 at1 μg/ml in PBS for nuclear staining. After incubation overnight at 4°C., cells were washed once with PBS to remove the excess of dye and 100μl of PBS was added to each well. Images were acquired at 20×magnification, 6 images per well, using the ImageXpress automatedmicroscope (Molecular Devices Inc.) and analyzed with MetaXpresssoftware to identify LC3-GFP foci. Foci area per cell values were usedto generate dose response curves and IC50 values were calculated usingthe non-linear fitting analysis in GraphPad Prism software.

The tested example compounds effectively inhibited autophagy in HOScells. The results of the assay are shown in Table 2 (Median IC₅₀ μMHOS-LC3).

TABLE 2 Median IC₅₀ values for the Vps34 assay and autophagy in HOScells assay. Example Compound Median IC50 (μM) Cellular assay 6 0.054 80.066 10 0.019 26 0.010 27 0.020 33 0.003 39 0.002 40 0.029 47 0.003 500.254 55 0.099 57 0.006 59 0.005

The invention claimed is:
 1. A compound of Formula (I)

wherein R1 is phenyl or monocyclic 5-6 membered heteroaryl, eachoptionally substituted with one or more substituents selected fromhalogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl,C1-C6haloalkoxy, amino, N-C1-C3alkylamino and N,N-diC1-C3alkylamino; R2is selected from hydrogen, C1-C3haloalkyl and C1-C3alkyl; R3 is selectedfrom A, phenyl and monocyclic heteroaryl, said phenyl and saidheteroaryl being each optionally substituted with one or more of R4, R5,R6 and R7; R4, R5, R6 and R7 are independently selected from halogen,C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl,C1-C6haloalkoxy, azetidine, amino, N-C1-C3alkylamino,N,N-diC1-C3alkylamino, NHSO2R8, SO2R9 and hydroxy; R8 is C1-C3haloalkylor C1-C3alkyl; R9 is selected from R10, C1-C6alkyl, amino,N-C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl,wherein said C1-C6alkyl and C1-C3alkoxyC1-C3alkyl being each optionallysubstituted with one R10 and/or one or more halogen; R10 is selectedfrom phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl,heterocyclyl, each optionally substituted with one or more R11; R11 isselected from halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl,amino, N-C1-C3alkylamino, N,N-diC1-C3 alkylamino and C1-C3 alkoxyC1-C3alkyl; A is

R12 is selected from hydrogen, halogen, COR13, C1-C6alkyl,C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl,C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from C1-C3alkoxy,N-C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyland 1-azetidinyl; Y is selected from CH2, S, SO, SO2, NR14, NCOR9,NCOOR15, NSO2R9, NCOCH2R9, O, or a bond; R14 is selected from H,C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl;R15 is selected from R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, andwherein said C1-C6alkyl and C1-C3alkoxyC1-C3alkyl being each optionallysubstituted with one R10 and/or one or more halogen; and Z is CH or N;or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein R2 is hydrogen; or a pharmaceutically acceptablesalt thereof.
 3. The compound according to claim 1, wherein R1 is phenylor a monocyclic 5-6 membered heteroaryl, each optionally substitutedwith one or more substituents selected from C1-C6alkyl, C3-C4cycloalkyl,and halogen; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1, wherein R1 is selected from phenyl,pyrimidinyl, oxazolyl, imidazolyl, pyrazolyl and thiazolyl, eachoptionally substituted with one or more substituents selected fromhalogen, C1-C6alkyl, C3-C4cycloalkyl, and C1-C6haloalkyl; or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1, wherein R3 is selected from A, phenyl, pyridyl, thienyl, furyl,pyrimidinyl and pyrazolyl, each optionally and independently substitutedwith one or more R4 or R5; or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1, wherein R3 is selectedfrom phenyl, pyridyl, morpholinyl, piperidyl, pyrrolidinyl, thienyl, andpiperazinyl, each optionally substituted with one or more substituentsselected from halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl;or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 1, wherein R4, R5, R6 and R7 are independently selected fromfluoro, chloro, C1-C3alkyl, C1-C3fluoroalkyl, cyclopropyl and SO2R9; ora pharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1, wherein R12 is selected from hydrogen, CON(CH3)2, C1-C3alkyl,CF3 and cyclopropyl; or a pharmaceutically acceptable salt thereof. 9.The compound according to claim 1, wherein R9 is selected from R10,N,N-diC1-C3alkylamino and methoxyC1-C3 alkyl, said C1-C3 alkyl beingoptionally substituted with one R10; or a pharmaceutically acceptablesalt thereof.
 10. The compound according to claim 1, wherein R10 isselected from phenyl, benzyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl,cyclopropyl, cyclopentyl, pyrrolidinyl, and tetrahydrofuryl, eachoptionally substituted with one or more methyl and/or fluoro; or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 1, wherein R1 is phenyl or a monocyclic 5-6 membered heteroaryleach optionally substituted with one or more substituents selected fromhalogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 ishydrogen; and R3 is phenyl or monocyclic 5-6 membered heteroaryl eachoptionally substituted with one or more substituents selected fromhalogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl; or apharmaceutically acceptable salt thereof.
 12. The compound according toclaim 1, wherein R1 is selected from phenyl, pyrimidinyl, oxazolyl,imidazolyl, or thiazolyl, each optionally substituted with one or moresubstituents selected from halogen, C1-C6alkyl, C1-C6haloalkyl, andC3-C4cycloalkyl; R2 is hydrogen; R3 is selected from phenyl, pyridyl,pyrazolyl, pyrrolidinyl, and thienyl, each optionally substituted withone or more substituents selected from halogen, C1-C6alkyl,C1-C6haloalkyl, C3-C4cycloalkyl; or A; Y is CH2, O, NSO2-C1-C6alkyl orNSO2-benzyl, wherein said benzyl is optionally substituted by one ormore halogen; and R12 is C1-C6alkyl or C1-C6haloalkyl; or apharmaceutically acceptable salt thereof.
 13. The compound according toclaim 1, wherein R1 is phenyl, 2-methylpyrimidin-4-yl, oxazol-2-yl,2-methylthiazol-4-yl, 2-methylpyrazol-3-yl, and 1-methylimidazol-4-yl;R2 is hydrogen; R3 is selected from 2-chlorophenyl, 3-pyridyl,4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl,3-(trifluoromethyl)¬morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoro-methyl)piperazin-1-yl,4-ethylsulfonyl-2-(trifluoro¬methyl)¬piperazin-1-yl;2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl,2-(trifluoromethyl)-pyridin-3-yl and1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; and Z is CH or N; or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 1, wherein R1 is phenyl, or 2-methylpyrimidin-4-yl; R2 ishydrogen; R3 is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl,1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl,3-(trifluoromethyl)¬morpholin-4-yl,4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluor-methyl)piperazin-1-yl,and 4-ethylsulfonyl-2-(trifluoro¬methyl)-piperazin-1-yl; and Z is CH orN; or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1, wherein the compound is selected from4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;4-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;4-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methyl-pyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;4-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoro¬methyl)¬phenyl]-1H-pyridin-2-one;4-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;and6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, carrier and/or excipient.
 17. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andanother anticancer agent selected from alkylating agents,antimetabolites, anticancer camptothecin derivatives, plant-derivedanticancer agents, antibiotics, enzymes, platinum coordinationcomplexes, tyrosine kinase inhibitors, hormones, hormone antagonists,monoclonal antibodies, interferons, and biological response modifiers.